NZ205291A - (1-oxo-2-pyridyl)-disulphide derivatives and animal feed compositions containing them - Google Patents
(1-oxo-2-pyridyl)-disulphide derivatives and animal feed compositions containing themInfo
- Publication number
- NZ205291A NZ205291A NZ205291A NZ20529183A NZ205291A NZ 205291 A NZ205291 A NZ 205291A NZ 205291 A NZ205291 A NZ 205291A NZ 20529183 A NZ20529183 A NZ 20529183A NZ 205291 A NZ205291 A NZ 205291A
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- Prior art keywords
- pyridyl
- oxo
- disulfide
- compound
- ppm
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Selected (1-oxo-2-pyridyl) disulfides are used as active ingredients in animal feed compositions and in methods for increasing the growth and feed efficiency of monogastric animals. A useful new compound of this invention is 2-carboxyphenyl (1-oxo-2-pyridyl) disulfide.
Description
New Zealand Paient Spedficaiion for Paient Number £05291
205291
Priority Date(s): . R.~.
Complete Specification Filed:
Class: .. ft??.*J jib.
Publication Date: ... • • P.O. Journal, No: .
ZEALAND PATENTS ACT, 1953
No: Date:
COMPLETE SPECIFICATION
FEED COMPOSITIONS CONTAINING A (1-0X0-2-PYRIDYL) DISULFIDE
we, SMITHLKINE BECKMAN CORPORATION, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, of One Franklin Plaza, Philadelphia, Pennsylvania 19103, United States of America hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by page -la-)
1
2052 9 1
- lo-
FEED COMPOSITIONS CONTAINING A (1-QXO-2-PYRIDYL) DISULFIDE
This invention comprises new animal feed compositions and methods using a (l-oxo-2-pyridyl)
disulfide as an active ingredient for altering the metabolic pattern in the digestive tract of monogastric animals, thereby, improving growth and feed efficiency of the animals.
Pyridyl disulfides have been described to be good topical antibacterial or antifungal agents for use in shampoos, wound dressings or soaps. Unsymmetrical disulfides for this use are disclosed in M. L. Douglas, U.S. Patent No. 4,049,665. Column 7, line 66 of the Douglas patent describes the concentration of disulfide in such topical compositions to be from 0.1-99%.
The animal feed compositions of this invention, which are supplemented by a (1-oxo-pyridyl) disulfide, are fed to monogastric, growing or fattening, meat-producing animals, especially swine and poultry.
For example, it is known to the art that, during assimilation of food, the production of volatile fatty acids and lactic acid in swine should be relatively low in the upper part of the digestive tract. On the other hand, glucose levels should be higher in the upper tract.
Lysine is an essential amino acid which is necessary for growth. Therefore, high levels of lysine are also
20529
1 desirable. Often, corn diets, which are naturally low in lysine, are supplemented with lysine.
The object of this invention is, therefore, to induce relatively low volatile fatty acid production in 5 the upper digestive tract together with a high glucose level, high lysine level and low lactic acid level by administering orally a nontoxic but effective quantity of a selected disulfide to the subject animals. This combination of factors is desired to insure that a larger 10 than normal quantity of energy and amino acid is available to the animals for growth from each unit of food in their diet.
The active ingredients, which are useful in the feed compositions and methods of this invention, are 15 illustrated by the structural formula:
in which:
R and R^~ are, each, hydrogen, C^_g-alkyl,
C^_g-alkoxy, C^_6~alkylthio, nitro, hydroxy,
halo such as chloro or bromo, carboxy, phenyl,
benzyl or benzylthio; and 2
R is phenyl, benzyl, pyridyl or 1-oxopyridyl, each of which has one or two substituents as defined for R and R^" above, C-^_^2~alkyl/ furyl, thienyl, glucosyl, (^..-^"alkeny! or carboxy-C^_g-alkyl.
A subgeneric group of preferred compounds to be used as active ingredients in this invention are those of
2
formula I in which R is not a pyridyl or 1-oxopyridyl. These may be described as unsymmetrical (l-oxo-2-pyridyl) 35 disulfides.
2052
Another aspect of this invention is the group of new chemical compounds which are represented by the following structural formula:
R1
^ S-S-P-CO-H II
N.^ 2
+
0
R and R1 are, each, hydrogen, C-^_g-alkyl, C^_g-alkoxy, C^_g-alkylthio, nitro, hydroxy,
halo such as chloro or bromo, carboxy, phenyl,
benzyl or benzylthio; and
P is alkylene of from 1-6 carbons or phenylene. The active ingredients of formulas I and II are prepared conveniently by the following reaction:
^XRl 2
+ X-S-R + I or II
R
.SH
+
0
12
in which R, R or R are as defined above; and X
is chloro or bromo.
2
The sulfenyl halide, X-S-R , is conveniently prepared and reacted, in situ, with the mercaptan starting material in an inert organic solvent at a temperature selected from the range of from 0° to the boiling point of the reaction mixture until completion. Base is added to the reaction material to neutralize the reaction product in order to isolate the free base form of the disulfide product. The base or the acid addition salt form of the disulfide, the latter preferably generated from the
20529
sulfenyl halide condensation which is outlined above, may be obtained by conventional isolation methods.
Alternatively, certain disulfide active ingredients used in this invention can be prepared by a sulfur/sulfur interchange reaction as described in the examples hereafter.
Also, included in this invention as active ingredients are the nontoxic, stable salts of the compounds of formulas I and II with acids known to the art to be useful for such purposes, for example, the hydrochloride, sulfate, sulfamate, phosphate, nitrate or acetate salts. The salt form, as noted above, may either be formed during the chemical reaction used in the preparation of the chemical ingredients or as a separate step, such as by reacting a compound of formula I with an excess of acid in an organic solvent. Also, if a carboxy group is present in the disulfide as in formula II compounds, a nontoxic alkali metal salt may be formed such as by shaking the disulfide with dilute potassium hydroxide, filtering and lyophilizing the filtrate. One skilled in the art will, therefore, recognize that certain compounds which are the active ingredients of this invention will have the capability to form salts and how such salts are prepared and isolated.
In addition to the salt forms of the compounds of this invention, other latentiated or prodrug forms of the active ingredients of formulas I and II may be used such as C^_g-alkyl or phenyl esters of the acid derivatives which are convertible within the animal's body to the active free acid parent. A specific example of such a latentiated derivative, which has been found to be very active as an active ingredient of this invention, is the 4-nitrophenyl ester of 2-carboxyethyl (l-oxo-2-pyridyl) disulfide.
The feed compositions of this invention comprise the normal feed rations of the meat producing animals
205291
supplemented by a quantity of an active ingredient of formula I, which is effective for improving the growth rate and feed efficiency of the animals but which is not toxic or noxious to a degree that the animals will reduce ingestion of the ration. The quantity of the active ingredient will vary, as is known to the art, with factors such as the cost of the ingredient, the species and the size of animal, the relative activity of the compound of formula I or the type of feed ration used as the basal feed.
Representative feed rations for swine and poultry are in the examples presented hereafter. Swine feed from weanling to fattening or finishing rations may be supplemented. Swine eat from about 2 lb. per day (for a 25 lb. pig) to 9 lb. per day (for a 150 lb. pig). Most rations are comprised of a corn base supplemented with legume silage, wheat bran, oats, barley, molasses or a protein supplement.
Poultry feeds comprise starter rations, broiler rations and laying rations. The rations are usually based on ground corn, corn meal or soybean meal. The broiler rations, often, contain high energy supplements such as added fats, proteins and vitamins. Turkey rations are similar, but comprise only a starting ration and a growing ration. Chickens or pheasants eat from .03-0.3 lbs. of feed per day, turkeys twice that much. Estimated intake of feed is dependent on the weight and age of the meat producing animal.
The active ingredients of formula I are mixed uniformly with such feed rations to give supplemented rations which are, then, fed as to custom which, is, most often, ad libitum. Conveniently, to do this, a premix of the supplemental growth promotant of this invention, optionally combined with or without other supplements known to this art such as an anthelmintic, a nitrogen source or an antibiotic such as virginiamycin or
2052
oxytetracycline, is prepared by the manufacturer for sale to the formulators or feed lot operators. The concentration of disulfide in the premix is usually from 5-75% by weight or a concentration 100-2000 times greater than that in the complete feed ration. The premix form may be liquid or solid. Premix vehicles are corn oil, cottonseed oil, molasses or distillers solubles to form a liquid premix preparation. Sucrose, lactose, corn meal, ground corn, flour, calcium carbonate or soybean meal are often used as bases for solid premix preparations. The premix composition is, then, mixed uniformly with whole ration which is commonly fed to the target animal. Such premix compositions are included in the term "feed compositions" as used herein.
The concentration of the disulfide of formula I in the complete ration is a nontoxic but active quantity chosen, for example, from a range of about 1-100 parts of active ingredient by weight per million parts of whole feed (ppm) or about 2-115 grams per ton. Advantageously, a quantity is chosen from the range of 5-50 ppm of a disulfide of formula I.
The percentage ratio by weight of active ingredient to feed suggested for this invention is selected from the range of about 0.0001-0.01%.
The method of using compositions of this invention comprises feeding them to growing, monogastric, meat-producing animals, especially swine and poultry, in an effective growth promoting but nontoxic quantity of such a compound having formula I. Other monogastric animals whose digestive tract features fermentation in a cecum or cecum-like chamber are rabbits and horses.
The supplemented feed rations described above are presented to the animal by methods known to the art. Ad libitum feeding in the pasture, pen or growing shed is most convenient to increase the growth rate of the animal and to increase the feed efficiency of the growing opera-
2052 9
tion. Alternatively, the same supplemented feeds may be given to ruminant animals, particularly when the disulfide of formula I is coated to bypass the upper stomach or rumen. Data presented in the in vitro working examples demonstrate that a selective effect as described above was not present in the rumen.
For example, a species active ingredient of this invention, 2-carboxyphenyl (l-oxo-2-pyridyl) disulfide, facilitated growth in chickens and pigs by as much as 6% with a 5-10% improvement in feed efficiency when used as described herein. A concentration of this species in whole feed ration which has proved very effective is about 15-25 ppm. 2-Carboxyethyl (l-oxo-2-pyridyl) disulfide gave similar results.
The following working examples are intended to illustrate this invention. All percentages are by weight. All temperatures are Centigrade.
EXAMPLE 1
A swine ration for growing hogs of 40-100 pounds body weight is prepared using the following formula:
Corn, ground 78.15%
Soybean oil meal, 44% 17.0%
Meat scraps, 50% 3.0%
Oyster shell flavor 0.4%
Bone meal 0.5%
Zinc oxide 0.01%
Vitamin A, B, B^2 & D optional supplement
The ration is supplemented to 100% with 20 ppm of 2-carboxyphenyl (l-oxo-2-pyridyl) disulfide distributed through a premix carrier. The ration is fed, ad libitum, to the penned growing or fattening swine.
205291
EXAMPLE 2
A chicken ration for broilers is prepared using the following formula:
Yellow corn meal
67.
%
Soybean oil meal
24.
00%
Menhaden fish meal
6.
00%
Steamed bone meal
1.
00%
Ground limestone
1.
00%
Iodized salt
0.
34%
% choline chloride
0.
13%
Vitamin
0.
%
Manganese sulfate
0.
02%
Vitamin mix
0.
06%
The ration is supplemented with 20 ppm of 2-carboxyphenyl (1-oxo-N-pyridyl) disulfide and fed ad libitum to the chickens.
EXAMPLE 3 In Vitro Swine Procedure
A. Methodology:
A Yorksire barrow is surgically prepared either with an ileal cannula, which is placed 15 cm. from the ileo-ceco-colic junction, or a cecal cannula, which is placed midway between the apex and origin of the cecum. The animal is fed 4 times daily to restrict intake to 4.5% of body weight in a 30 kg animal or 2.5% of body weight in a 100 kg animal. The swine grower ration is:
% w/w lbs/ton
Medium ground shelled corn 70.60 1412
Soybean meal, 44% 22.00 440
Dehydrated alfalfa meal, 17% 4.50 90
Calcium propionate 0.15 3
Vitamin/mineral premix 2.75 55
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Sampling of the material, via the cannula, begins 150-180 minutes following the first morning feeding and continues any time from 30-120 minutes thereafter, depending on the quantity of material needed. The sample is maintained in crushed ice, no cooler than 5°, and is gassed continuously with carbon dioxide. The collected material is filtered. The filtrate is the inoculum used for incubations of the test and control samples. The gassed inoculum, 2.25 ml, is placed in each of 10 gassed test tubes, each containing 0.75 ml of a nutrient solution and 0.5 mg of each test compound. Four blank control tubes, along with the test compound tubes, are incubated 5 hours at 37° with agitation. Four more killed tubes are included which are not incubated.
The tubes are each treated with 0.60 ml of a 25% solution of metaphosphoric acid, then, stored at -4°
until analysis. Samples are thawed and centrifuged for 25 minutes at 20,000 r.p.m. The supernatent liquid is decanted, sampled for gas chromatography and automatic analyzing. The results are fed into a computer for finishing to give figures in which the blank control value is 100%. Virginiamycin is used as a positive control.
B. Results: Compound
VFA
LYS
GLU
LAC*
1. 2-Carboxyphenyl (l-oxo-2-pyridyl) disulfide
% of control values
Ileal a)
166.7
ppm
49
107
999
129
b)
166.7
ppm
57
160
235
79
c)
166.7
ppm
36
176
190
100
d)
166.7
ppm
385
152
* VFA refers to the total of volatile fatty acids, namely acetate, propionate, isobutyrate, butyrate, isovalerate and valerate. LYS is lysine, GLU is glucose and LAC is L-lactic acid.
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Compound VFA LYS GLU LAC
% of control values Representative Virginiamycin control runs Ileal a) 166.7 ppm
39
289
153
23
16.7 ppm
85
212
153
21
1.67 ppm
147
134
131
39
4-Fluorophenyl (l-oxo-2-pyridyl) disulfide hydrochloride Ileal a) 166.7
ppm
19
246
181
106
b) 166.7
ppm
57
200
370
56
c) 166.7
ppm
56
104
925
142
(2,3,4,6-
Tetra-O-acetyl-
-D-glucosyl)
( 1-OXO-2-;
pyr idy:
disulfide hydrobromide
Ileal
a) 166.7
ppm
64
174
224
78
b) 166.7
ppm
147
144
105
c) 166.7
ppm
29
123
139
104
Rumen (Fistulated cattle)
d) 50.0
ppm
70
83
0
364
.0
ppm
104
96
28
249
0.5
ppm
108
128
0
107
S-D-Glucosyl (l-oxo-2-pyridyl) disulfide dihydrate Ileal a) 166.7 ppm
23
321
152
52
16.7 ppm
42
294
152
47
1.67 ppm
106
114
119
78
b) 166.7 ppm
29
107
117
102
Dodecyl (l-oxo-2-pyridyl)
disulfide
Ileal
a) 166.7 ppm
39
148
159
105
16.7 ppm
50
127
138
107
1.67 ppm
68
134
118
104
b) 166.7 ppm
26
126
0
141
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1 Compound VFA LYS GLU LAC
6. (5-Bromo-l-oxo-2-pyridyl) disulfide
% of control values
Ileal a)
166.7 ppm
69
81
353
150
16.7 ppm
80
90
250
110
1.67 ppm
82
92
155
101
b)
166.7 ppm
44
122
156
135
c)
166.7 ppm
49
119
130
125
d)
166.7 ppm
103
94
134
94
7. (l-Oxo-2-pyridyl) disulfide Ileal a) 166.7
ppm
212
203
70
b) 166.7
ppm
17
206
180
16.7
ppm
19
185
180
1.67
ppm
93
121
113
c) 166.7
ppm
4
143
133
d) 166.7
ppm
41
145
625
118
16. 7
ppm
39
134
649
118
1. 67
ppm
84
110
415
110
Rumen
e) 50.0
ppm
16
197
999
518
f) 50.0
ppm
65
333
17
8. 2-Mercapto-l-oxopyridine
Ileal a)
333. 3
ppm
129
100
101
b)
166.7
ppm
19
175
505
94
c)
166.7
ppm
31
100
138
101
C. Conclusions:
These representative results demonstrate the pro jected spectrum of biological activity of the disulfides, especially compared with that of the parent 1-oxopyridine mercaptan (8). Inhibition of volatile fatty acid formation is particularly to be noted. Similar studies in 35 the rumen of fistulated cattle, certain of which are noted above, demonstrate that the selective effect is limited to monogastric animals.
205291
EXAMPLE 4 Chick Growth Study
A. Methodology:
512 one day old broiler chicks, selected for weight, health and sex, are housed in an environmentally controlled room with temperature at 80°F and humidity at 40%. Chicks are fed ad libitum. Water is offered ad libitum. A rye or corn basal ration is fed during the acclimation period (days 1 and 2), then, mixed with the compound under test or control conditions on days 3-17. Either 8 or 16 chicks are used for each test or control group.
Basal Rye Diet
Diet Ingredients
(% w
/w)
(lbs/ton)
Ground Rye (fine grind)
54.
6
1092
Soybean Meal (49% protein)
27
540
Meat & Bone meal (50% protein)
200
Dehydrated Alfalfa meal
1.
Fat, animal
4
80
Dried Whey (or lactose)
1
Ground Limestone
0.
67
13.4
Dicalcium Phosphate
0.
50
Iodized salt
0.
23
4.6
Vitamin premix
0.
175
*
Trace mineral premix
0.
DL methionine (98%)
0.
Choline Chloride (50% aqueous sol.) 0.150** 3
* Vitamin premix will be mixed into diets when test chemicals are added. 87.5 g vitamin premix/49,912.5 g of basal rye diet.
** Since choline is added as a 50% aqueous solution, percentage in diet is doubled.
20529 1
B. Results:
% of Control
Chemical
Weight (17 day) Feed/Gain (3-17 day)
1. Virginiamycin a. 10 ppm (rye)
b. 50 ppm (rye)
c. 10 ppm (rye)
107.1 127.8 97.7
2. l-Oxo-2-pyridyl disulfide
2.5 ppm 1 ppm 10 ppm 1 ppm 10 ppm 20 ppm 1 ppm 10 ppm f. 2.5 ppm g. 2.5 ppm a.
b.
d.
e.
(corn)
(rye)
(rye)
(rye)
(rye)
(rye)
(rye)
(corn) (corn)
102. 2 100. 2 94.7
97. 96, 96, 100, 94 102,
6 2 2
7 2
96.5 88.5 100. 4
111. 4 98. 2 101.9 95.4
103. 96, 98, 101, 114,
1 6
2 9 4
103.0
99.8 (31 days)
3. 4-Fluorophenyl (1-oxo-2-pyridyl) disulfide hydrochloride a. 5 ppm (rye)
b. 10 ppm (rye)
c. 5 ppm (rye)
99.4 98.0 99.4
87.5 97.8 87. 5
a.
b.
2-Carboxyphenyl (l-oxo-2-pyridyl) disulfide
ppm (rye)
2 ppm (rye)
ppm 10 ppm 50 ppm c. 5 ppm (rye)
ppm 50 ppm d. 10 ppm (rye)
50 ppm
100 ppm e. 10 ppm (rye)
f. 6 ppm (rye)
2,3,4,6-Tetra-0-acetyl-B-D-glucosyl (l-oxo-2-pyridyl) disulfide hydrobromide
103.6
100.1
100.7
102. 2
101.6
100. 6
102.8
101.3
98.6
102.6
97. 2
100.0
99.8
96.6
86.9
107.5
104.2
94. 2
105.3
88.8
54.1
179.1
99.5
98.8
106.0
94.7
a. 10 ppm (rye)
95. 4
101.6
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1 Conclusions:
The tests in chickens confirm the enhancement of either growth rate or increase in feed efficiency of the poultry feed compositions. The 17 day growth rate should 5 be positive and the 3-17 day feed efficiency should be negative. Certain test results are negative due to biological variability in our early or initial screens.
EXAMPLE 5
A. Methodology:
A standard corn based, pre-starter feed composition for feeding 2 week old post weanling pigs was supplemented with 20 ppm of the bis(oxo-2-pyridyl) disulfide. The animal group comprised 15 replications, each 15 containing 3 treatments, which were untreated corn ration as negative control, virginiamycin at 20 ppm as positive control and the stated test ration. Each replication contained 8 treatment groups, in turn, comprising 2 pigs per pen.
The following data summarizes the results:
B. Results:
Control Virginiamycin (l-oxo-2-pyridyl)
disulfide
Dose (ppm) - 20 10
Starting wt (Kg) 22.3 23.4 22.2
Average daily gain .720 + .066 .730 + .066 (0-21 day)
Average daily gain .725 .746 .716
Feed/gain 2.95 2.80 2.84
(0-41 day)
.verage dai Feed/gain (0-63 day)
Average daily gain .749 .747 .723
Feed/gain 3.36 3.32 3.26
2052 91
EXAMPLE 6
A. Methodology:
Replications of swine each containing 3 treatments test compositions containing 20 ppm of 2-carboxyphenyl (l-oxo-2-pyridyl) disulfide (CPD).
B. Results:
Control Virginiamycin CPD
Dose - 10 ppm 20 ppm
Starting wt 23.7 22.51 23.17
Average daily gain .704 .697 .690
Feed/gain 2.70 2.61 2.65
(0-21 day)
Average daily gain .691 .719 .720
Feed/gain 2.85 2.82 2.83
(0-35 day)
C. Conclusions:
2-Carboxyphenyl (l-oxo-2-pyridyl) disulfide (CPD) demonstrated increased growth and feed efficiency roughly 20 equivalent with that of virginiamycin.
EXAMPLE 7
A. Methodology:
Ten Yorkshire barrows were fed a standard ration (5 pigs) or the same ration supplemented with 100 ppm of 2-25 carboxyethyl (l-oxo-2-pyridyl) disulfide (5 pigs) for 21
days. Pigs were paired into 5 replicates based on starting weight and rate of gain from delivery to the feeding site until the study began.
B. Results:
Ave. Ave. Ave.
Starting Final Daily n wt. (kg) wt. (kg) Gain (kg) Feed/Gain
Control 5 28. 2 44. 05 0. 755 2.851
27.8 44.0 0. 771 (102. 2%) 2.701 (94.8%)
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C. Comments:
No outward toxic effects were observed.
EXAMPLE 8
^ Chemical Preparations
A. A round bottom flask equipped with mechanical stirrer was charged with 3.08 g (0.020 mol) of 2-mercapto-benzoic acid and 100 ml of anhydrous ether. The mixture was stirred until the thiosalicylate dissolved. To this
^ solution was added 4.45 g (0.025 mol) of N-bromosuccini-
mide. After 60 minutes, the orange solution which contains 2-carboxybenzenesulfenyl bromide was decanted from the succinimide precipitate. To the orange etherate solution was added 2.5 g (0.020 mol) of 2-mercaptopyridine-N-oxide.
After 90 minutes of vigorous agitation at 25°, a 85% yield of 2-carboxyphenyl (l-oxo-2-pyridyl) disulfide was collected by filtration. The disulfide had a melting point of 145-147°. Compound is further purified by recrystallization from 8:1:1:1 (8 parts methanol to 1 part
methylene chloride, ether and acetic acid respectively) solution. The purified compound had a melting point of 145-146°.
Anal. Calcd. for C12HgN03S2: C, 51.60;
H, 3.25? N, 5.01; S, 22.95. Found: C, 51.47; H, 3.28;
N, 5.12; S, 22.82.
The above procedure is repeated using 3-mercapto-benzoic acid and 4-mercaptobenzoic acid to give, respectively, 3-carboxyphenyl (l-oxo-2-pyridyl) disulfide and 4-carboxyphenyl (l-oxo-2-pyridyl) disulfide.
^ B. In a round bottom flask was placed 500 mg
(0.0027 mols) of N-bromosuccinimide, 1 g (0.0028 mol) of g-thioglucose tetraacetate and 50 ml of toluene. The mixture was mechanically stirred for 20 minutes while the temperature was lowered to 0°. To this cooled solution is
"?5
added, from a dropping funnel, 340 mg (0.0027 mol) of 2-
205291
mercaptopyridine-N-oxide in 50 ml of toluene. After 20 minutes at 5° or below, the temperature was raised to 60° and stirring was continued for an additional 20 minutes. The reaction mixture was cooled to room temperature and stirred overnight. A white precipitate was collected and thin layer chromatography showed one spot (using a silica gel plate with eluting solvent of 8:1:1:1 methylene chloride:methanol; ethyl ether; acetic acid). Crude metling point was 160-163°. The product was further purified by recrystaliization from methanol and anhydrous ether (1:2 ratio). The final product was vacuum oven dried for 24 hours to give preparation of (2,3,4,6-tetra-O-acetyl-g-D-glucosyl) (l-oxo-2-pyridyl) disulfide hydrobromide, m.p. 154-155°.
Anal. Calcd. for C-^gH2-jNOj_gS2*HBr:
C, 40.00; H, 4.24; N, 2.45. Found: C, 39.70; 40.12; H, 4.17, 4.17; N, 2.26, 2.39.
C. (2,3,4,6-Tetra-O-acetyl-6-D-glucosyl) (1-oxo-2-pyridyl) disulfide (250 mg) was deacetylated by dissolving the compound in methanol and bubbling in hydrogen chloride gas. After 10 minutes, the gas was removed and mixture stirred overnight. Methanol was removed by rotary evaporation and clear solid is dried under nitrogen vacuum. The compound has a melting point of 87°; ( $-D-glucosyl) (1-oxo-pyridyl) disulfide dihydrate.
Anal. Calcd. for C,, H, .-NO.-S,, • 2. 5 H„0:
11 15 6 2 2
C, 36.06; H, 4.95; N, 3.82. Found: C, 36.11; H, 4.65; N, 3.78.
D. N-chlorosuccinimide (4.39 g) was added in several portions to a cold (0°) solution of 4.26 g (0.032 mol) of 97% £—fluorothiophenol and 100 ml of toluene.
After 40 minutes stirring at room temperature, the orange solution was collected by filtration, cooled to 0° while a solution of 2.11 g of mercaptopyridine-N-oxide in 100 ml of ether was added. After stirring at room temperature
Claims (1)
10 20 0 5291 - 18 - for 20 minutes, the product was collected, washed and purified over a silica gel column to give 5.27 g of 4-fluorophenyl (l-oxo-2-pyridyl) disulfide, m.p. 94-96°. Anal. Calcd. for C^HgNOSF • HC1: C, 52.16; H, 3.18; N, 5.53. Found: C, 52.07; H, 3.27; 5.63. E. Using the same procedure as above, dodecyl (1-oxo-2-pyridyl) disulfide hydrobromide was obtained; m.p. 103-105°. Anal. Calcd. for C^H2gNOS2 * HBr: C, 42.97;;H, 7.40; N, 3.43. Found: C, 50.40, 50.28; H, 7.07, 7.30; N, 3.40, 3.38.;F. A mixture of 8.6 g (0.034 mol of bis(l-oxo-2-pyridyl)-disulfide, 6.9 (0.056 mol) of 3-mercaptopropionate and 400 ml of chloroform was heated at reflux overnight.;^ Cooling separated a product contaminated with disulfide starting material. The mixture was purified by recrystaliization from hot methanol to give 2-carboxyethyl (l-oxo-2-pyridyl) disulfide, m.p. 162-163°.;25;Anal. Calcd. for CgHgN02S2: C, 41.56; N, 3.89; N, 6.06; S, 27.70. Found: C, 51.54; H, 3.94; N, 6.05; S, 27.85.;The 4-nitrophenyl ester derivative melts at 109-;111°.;Anal. Calcd. for (-^^H^2N2<^5S2: ^7.27; H, 3.43; N, 7.95. Found: C, 47.89; H, 3.60; N, 7.94.;30;35;- 19 -;205191;WHAT /WE CLAIM IS:;1. An animal feed composition supplemented by a quantity of a compound of the formula:;S-S-R;in which:;R and R1 are, each, hydrogen, C^_g-alkyl,;C^^-alkoxy, C^_g-alkylthio, nitro, hydroxy, halo,;carboxy, phenyl, benzyl or benzylthio; and;2;R is a phenyl, benzyl, pyridyl, 1-oxo-pyridyl, each of the former has one or two optional substituents as defined for R and R1 above,;Ci_i2~alkyl» furyl, thienyl, glucosyl, alanyl, C^^-alkenyl or carboxy-C^_g-alkyl; a nontoxic,;stable salt thereof; or a latentiated derivative thereof; which is effective for increasing the growth rate and feed efficiency of a meat producing monogastric animal but which is nontoxic to said animal.;2. The composition of claim 1 in which quantity of the compound is selected from the range of from 1-100 parts of compound per million parts of composition by weight.;3. The composition of claim 1 in which the compound is a carboxyphenyl (l-oxo-2-pyridyl) disulfide.;4. The composition of claim 1 in which the compound is 2-carboxyphenyl (l-oxo-2-pyridyl) disulfide which is present in from 15-25 parts by weight of compound per million parts by weight of composition.;5. The composition of claim 1 in which the compound is 2-carboxyethyl (l-oxo-2-pyridyl) disulfide.;- 20 -;205291;6. A compound of the formula:;+;0;in which:;R and R^" are, each, hydrogen, C^_g-alkyl, C^_g-alkoxy, C^g-alkylthio, nitro, hydroxy, halo, carboxy, phenyl, benzyl or benzylthio? and;P is alkylene of 1-6 carbons or phenylene, or a nontoxic salt thereof.;7/ The compound of claim 6 being 2-carboxy-phenyl (l-oxo-2-pyridyl) disulfide.;8. The compound of claim 6 being 2-carboxy-ethyl (l-oxo-2-pyridyl) disulfide.;9. The method of improving weight gain and feed efficiency in animals comprising feeding a compound or composition of claims 1-8.;10. A. composition as claimed in any one of claims;2 to 5 substantially as hereinbefore described with reference to any example thereto.;11. A compound as claimed in any one of claims 6;to 8 substantially as hereinbefore described with, reference to any example thereto.;12. A, method as claimed in claim 9 when performed substantially as hereinbefore described.;BATED TH18'SisVI>AY 0Oc.W l&'SS" A, J. PARK & SON;AGENTS FOR THE APPLICANTS;*/ ,Us - r-iKDVS®7 V.,vV
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/420,678 US4505917A (en) | 1982-09-21 | 1982-09-21 | Feed compositions containing a (1-oxo-2-pyridyl) disulfide |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ205291A true NZ205291A (en) | 1986-01-24 |
Family
ID=23667425
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ205291A NZ205291A (en) | 1982-09-21 | 1983-08-16 | (1-oxo-2-pyridyl)-disulphide derivatives and animal feed compositions containing them |
Country Status (14)
Country | Link |
---|---|
US (1) | US4505917A (en) |
EP (1) | EP0104836B1 (en) |
JP (1) | JPS5973569A (en) |
AT (1) | ATE16678T1 (en) |
AU (1) | AU556472B2 (en) |
CA (1) | CA1191141A (en) |
DE (1) | DE3361352D1 (en) |
DK (1) | DK428583A (en) |
ES (1) | ES8506631A1 (en) |
GR (1) | GR79675B (en) |
IE (1) | IE55969B1 (en) |
NZ (1) | NZ205291A (en) |
PT (1) | PT77271B (en) |
ZA (1) | ZA836094B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5057510A (en) * | 1983-09-16 | 1991-10-15 | Olin Corporation | Use of selected pyridine-2-thione-N-oxide compounds as growth promoters for poultry |
US7282590B2 (en) * | 2004-02-12 | 2007-10-16 | The Research Foundation Of State University Of New York | Drug conjugates |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773770A (en) * | 1968-09-30 | 1973-11-20 | Procter & Gamble | Process for preparing pyridine n-oxide carbanion salts and derivatives thereof |
US3954781A (en) * | 1975-04-22 | 1976-05-04 | Olin Corporation | Process for preparing bis(2-pyridyl-1-oxide) disulfide |
US4049665A (en) * | 1975-12-24 | 1977-09-20 | Colgate-Palmolive Company | Unsymmetrical disulfides as antimicrobial agents |
US4258193A (en) * | 1978-07-13 | 1981-03-24 | Toyo Jozo Kabushiki Kaisha | Disulfide derivatives having S--S exchange reactivity |
-
1982
- 1982-09-21 US US06/420,678 patent/US4505917A/en not_active Expired - Fee Related
-
1983
- 1983-08-11 CA CA000434386A patent/CA1191141A/en not_active Expired
- 1983-08-16 NZ NZ205291A patent/NZ205291A/en unknown
- 1983-08-17 AU AU18073/83A patent/AU556472B2/en not_active Ceased
- 1983-08-18 ZA ZA836094A patent/ZA836094B/en unknown
- 1983-08-30 PT PT77271A patent/PT77271B/en not_active IP Right Cessation
- 1983-09-14 ES ES525605A patent/ES8506631A1/en not_active Expired
- 1983-09-15 DE DE8383305392T patent/DE3361352D1/en not_active Expired
- 1983-09-15 AT AT83305392T patent/ATE16678T1/en active
- 1983-09-15 EP EP83305392A patent/EP0104836B1/en not_active Expired
- 1983-09-16 JP JP58172056A patent/JPS5973569A/en active Pending
- 1983-09-19 GR GR72471A patent/GR79675B/el unknown
- 1983-09-20 DK DK428583A patent/DK428583A/en not_active Application Discontinuation
- 1983-09-20 IE IE2200/83A patent/IE55969B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
CA1191141A (en) | 1985-07-30 |
EP0104836A1 (en) | 1984-04-04 |
ZA836094B (en) | 1984-07-25 |
JPS5973569A (en) | 1984-04-25 |
US4505917A (en) | 1985-03-19 |
IE832200L (en) | 1984-03-21 |
GR79675B (en) | 1984-10-31 |
PT77271A (en) | 1983-09-01 |
DE3361352D1 (en) | 1986-01-09 |
DK428583D0 (en) | 1983-09-20 |
ES525605A0 (en) | 1985-08-01 |
ATE16678T1 (en) | 1985-12-15 |
PT77271B (en) | 1986-02-04 |
EP0104836B1 (en) | 1985-11-27 |
ES8506631A1 (en) | 1985-08-01 |
DK428583A (en) | 1984-03-22 |
IE55969B1 (en) | 1991-03-13 |
AU556472B2 (en) | 1986-11-06 |
AU1807383A (en) | 1984-03-29 |
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